Submissions for variant NM_000081.4(LYST):c.3898A>G (p.Ile1300Val)

gnomAD frequency: 0.00021  dbSNP: rs199855658

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000319478	SCV000355761	uncertain significance	Chédiak-Higashi syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000319478	SCV000745219	likely benign	Chédiak-Higashi syndrome	2016-10-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000319478	SCV000834702	uncertain significance	Chédiak-Higashi syndrome	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1300 of the LYST protein (p.Ile1300Val). This variant is present in population databases (rs199855658, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with LYST-related conditions. ClinVar contains an entry for this variant (Variation ID: 296399). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LYST protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000319478	SCV003815297	uncertain significance	Chédiak-Higashi syndrome	2019-10-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987499	SCV004803513	uncertain significance	not specified	2024-01-18	criteria provided, single submitter	clinical testing	Variant summary: LYST c.3898A>G (p.Ile1300Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 250752 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in LYST causing Chediak-Higashi Syndrome (0.00021 vs 0.0011), allowing no conclusion about variant significance. c.3898A>G has been reported in the literature in individuals affected with multiple sclerosis, but the variant was also identified in healthy controls (e.g., Traboulsee_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Chediak-Higashi Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 28337550). ClinVar contains an entry for this variant (Variation ID: 296399). Based on the evidence outlined above, the variant was classified as uncertain significance.
Clinical Genetics, Academic Medical Center	RCV001699289	SCV001921634	likely benign	not provided		no assertion criteria provided	clinical testing